Method for producing solid galenic formulations using a crosslinked non-thermoplastic carrier

ABSTRACT

The invention concerns a method for producing solid galenic formulations which consists in: forming a processable paste comprising a) 50 to 99.4 wt. % of at least one non-thermoplastic carrier, b) 0.5 to 30 wt. % of at least an adjuvant selected among thermoplastic polymers, lipids, sugar alcohols and solubilizing agents, c) 0.1 to 49.5 wt. % of at least one active principle, at a temperature not less than the softening temperature of the adjuvant but rising to at least 70° C.; then in cooling the resulting paste. Said solid galenic formulations quickly disintegrate in an aqueous medium.

The present invention relates to a process for producing fast-releasesolid dosage forms.

The production of solid dosage forms by melt extrusion, i.e. a processin which a melt of a polymeric binder and of an active ingredient isextruded, and the extrudate is shaped to the desired drug form, isknown, see, for example, EP-A 240 904, EP-A 240 906, EP-A 337 256 andEP-A 358 105. This process permits the preparation of slightly solubleactive ingredients in the form of solid solutions. The active ingredientis present in the solid solutions in amorphous form and can therefore beabsorbed more easily than the crystalline active ingredient. However,the dissolution of the dosage form and the release of the activeingredient takes place only at the surface of the dosage form. In manycases, however, rapid disintegration of the dosage form is desired.

EP-B 0078430 discloses a process for producing fast-releasepharmaceutical preparations comprising dihydropyridine,polyvinylpyrrolidone and insoluble carriers such as crosslinkedpolyvinylpyrrolidone, where the active ingredient and thepolyvinylpyrrolidone are dissolved in an organic solvent, and thesolution is granulated with the carrier. This process cannot, however,be directly applied to other slightly soluble active ingredients becausea suitable physiologically tolerated solvent does not exist for allactive ingredients and/or complete removal of the solvent is impossibleor possible only in a troublesome manner.

GB 2 153 676 proposes the loading of water-insoluble polymers such ascrosslinked polyvinylpyrrolidone with an active ingredient by mixing thepolymer with the active ingredient and heating to the melting point ofthe active ingredient. This procedure has the disadvantage that manyactive ingredients cannot be melted without decomposition.

EP-A 0 446 753 discloses the loading of crosslinked polymers with anactive ingredient by treating the polymer with a solution of the activeingredient, or grinding the polymer and the active ingredient with highenergy input. The process has the disadvantage that it cannot be carriedout continuously.

DE-A 44 13 350 describes slow-release matrix pellets consisting of anactive ingredient, 5 to 50% by weight of a water-insoluble polymer suchas ethylcellulose, 5 to 45% by weight of a lipophilic component, 3 to40% by weight of a gel former such as hydroxypropylcellulose, and whereappropriate formulation aids. The slow-release matrix pellets can beproduced by melt extrusion.

It is an object of the invention to indicate a universally applicableprocess which allows dosage forms with rapid release in particular ofslightly soluble active ingredients to be produced without the need touse organic solvents or to melt the active ingredient.

The present invention therefore relates to a process for producing soliddosage forms, in which a moldable composition which comprises

-   a) 50 to 99.4% by weight, preferably 60 to 80% by weight, of at    least one crosslinked nonthermoplastic carrier,-   b) 0.5 to 30% by weight, preferably 5 to 20% by weight, of at least    one adjuvant selected from thermoplastic polymers, lipids, sugar    alcohols, sugar alcohol derivatives and solubilizers and-   c) 0.1 to 49.5% by weight, preferably 5 to 25% by weight, of at    least one active ingredient,    is formed at a temperature at or above the softening point of the    adjuvant, but at least 70° C., preferably 100 to 180° C., and    subsequently cooled.

In preferred embodiments, the composition comprises

-   a) 50 to 90% by weight, preferably 60 to 80% by weight, of at least    one crosslinked nonthermoplastic carrier,-   b1) 5 to 30% by weight, preferably 7 to 15% by weight, of at least    one thermoplastic polymer,-   b2) 0.5 to 20% by weight, preferably 5 to 10% by weight, of at least    one solubilizer,-   c) 0.1 to 45.5% by weight, preferably 5 to 25% by weight, of at    least one active ingredient.

The crosslinked nonthermoplastic carrier acts as disintegrant whichbrings about rapid disintegration of the dosage form in an aqueousenvironment such as gastric juice. It is surprisingly possible toproduce the dosage forms, which comprise a predominant proportion of acrosslinked nonthermoplastic carrier, in the absence of solvents througha process similar to melt extrusion if particular adjuvants areadditionally used. “Adjuvant” or “adjuvants” mean excipients whichremain in the dosage form and are not merely added during production andare removed again in a later processing step.

Dosage forms mean all forms suitable for use as medicaments, inparticular for oral administration, plant-treatment compositions, animalfeeds and dietary supplements. They include for example tablets of anyshape, pellets or granules.

The crosslinked nonthermoplastic carrier is a natural, semisynthetic orfully synthetic polymer which is crosslinked to a degree of crosslinkingsuch that it has no thermoplastic properties. It is usually insoluble inwater but swellable in water. The nonthermoplastic carrier is preferablyselected from crosslinked polyvinylpyrrolidone and crosslinked sodiumcarboxymethylcellulose. Crosslinked polyvinylpyrrolidone is mostpreferred. Suitable products are described for example in the USPharmacopeia (USP NF).

Besides the active ingredient and the crosslinked nonthermoplasticcarrier, there is also employed in the process of the invention at leastone adjuvant selected from thermoplastic polymers, lipids, sugaralcohols, sugar alcohol derivatives and solubilizers.

Examples of suitable thermoplastic polymers are polyvinylpyrrolidone(PVP), copolymers of N-vinylpyrrolidone and vinyl acetate or vinylpropionate, copolymers of vinyl acetate and crotonic acid, partiallyhydrolyzed polyvinyl acetate, polyvinyl alcohol,polyhydroxyalkylacrylates, polyhydroxyalkyl-methacrylates, polyacrylatesand polymethacrylates (Eudragit types), copolymers of methylmethacrylate and acrylic acid, polyethylene glycols, alkylcelluloses,especially methylcellulose and ethylcellulose, hydroxyalkylcelluloses,especially hydroxypropylcellulose (HPC), hydroxyalkylalkylcelluloses,especially hydroxypropylmethylcellulose (HPMC), cellulose esters such ascellulose phthalates, in particular cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcelluloseacetate succinate (HPMCAS). Of these, homo- or copolymers ofvinylpyrrolidone are particularly preferred, e.g. polyvinylpyrrolidonewith Fikentscher K values of from 12 to 100, preferably 17 to 30, orcopolymers of 30 to 70% by weight of N-vinylpyrrolidone (VP) and 70 to30% by weight of vinyl acetate (VA), such as, for example, a copolymerof 60% by weight VP and 40% by weight VA.

The thermoplastic polymers preferably have a softening temperature offrom 60 to 180° C., in particular 70 to 130° C.

Suitable sugar alcohols are sorbitol, xylitol, mannitol, maltitol; asuitable sugar alcohol derivative is isomalt.

Suitable lipids are fatty acids such as stearic acid; fatty alcoholssuch as cetyl or stearyl alcohol; fats such as animal or vegetable fats;waxes such as carnauba wax; or mono- and/or diglycerides orphosphatides, especially lecithin. The fats preferably have a meltingpoint of at least 50° C. Triglycerides of C₁₂, C₁₄, C₁₆ and C₁₈ fattyacids are preferred.

Solubilizers mean pharmaceutically acceptable nonionic surface-activecompounds. Suitable solubilizers include sorbitan fatty acid esters,polyalkoxylated fatty acid esters such as, for example, polyalkoxylatedglycerides, polyalkoxylated sorbitan fatty acid esters or fatty acidesters of polyalkylene glycols; or polyalkoxylated ethers of fattyalcohols. A fatty acid chain in these compounds usually comprises 8 to22 carbon atoms. The polyalkylene oxide blocks comprise on average from4 to 50 alkylene oxide units, preferably ethylene oxide units, permolecule.

Suitable sorbitan fatty acid esters are sorbitan monolaurate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitantristearate, sorbitan trioleate, sorbitan monostearate, sorbitanmonolaurate or sorbitan monooleate.

Examples of suitable polyalkoxylated sorbitan fatty acid esters arepolyoxyethylene(20)sorbitan monolaurate, polyoxyethylene (20)sorbitanmonopalmitate, polyoxyethylene(20)sorbitan monostearate,polyoxyethylene(20)sorbitan monooleate, polyoxyethylene(20)sorbitantristearate, polyoxyethylene(20)sorbitan trioleate,polyoxyethylene(4)sorbitan monostearate, polyoxyethylene(4)sorbitanmonolaurate or polyoxyethylene(4)sorbitan monooleate.

Suitable polyalkoxylated glycerides are obtained for example byalkoxylation of natural or hydrogenated glycerides or bytransesterification of natural or hydrogenated glycerides withpolyalkylene glycols. Commercially available examples arepolyoxyethylene glycerol ricinoleate 35, polyoxyethylene glyceroltrihydroxystearate 40 (Cremophor® RH40, BASF AG) and polyalkoxylatedglycerides obtainable under the proprietary names Gelucire® andLabrafil® from Gattefosse, e.g. Gelucire® 44/14 (lauroyl macrogol 32glycerides prepared by transesterification of hydrogenated palm kerneloil with PEG 1500), Gelucire® 50/13 (stearoyl macrogol 32 glyceridesprepared by transesterification of hydrogenated palm oil with PEG 1500)or Labrafil M1944 CS (oleoyl macrogol 6 glycerides prepared bytransesterification of apricot kernel oil with PEG 300).

A suitable fatty acid ester of polyalkylene glycols is for example PEG660 hydroxystearic acid (polyglycol ester of 12-hydroxystearic acid (70mol %) with 30 mol % ethylene glycol).

Suitable polyalkoxylated ethers of fatty alcohols are for examplemacrogol 6 cetylstearyl ether or macrogol 25 cetylstearyl ether

Besides these, it is possible additionally to use conventionalpharmaceutical excipients, the total amount of which may be up to 20% byweight based on the dosage form. These include:

extenders or fillers such as lactose, cellulose, silicates or silica,

lubricants such as magnesium stearate and calcium stearate, sodiumstearyl fumarate,

colorants such as azo dyes, organic or inorganic pigments or colorantsof natural origin,

stabilizers such as antioxidants, light stabilizers, hydroperoxidedestroyers, radical scavengers, stabilizers against microbial attack.

Active ingredients mean for the purposes of the invention all substanceswith a desired physiological effect on the human or animal body orplants. They are in particular active pharmaceutical ingredients. Theamount of active ingredient per dose unit may vary within wide limits.It is usually chosen so that it is sufficient to achieve the desiredeffect. Combinations of active ingredients can also be employed. Activeingredients for the purposes of the invention are also vitamins andminerals. Vitamins include the vitamins of the A group, or the B group,by which are meant besides B₁, B₂, B₆ and B₁₂ and nicotinic acid andnicotinamide also compounds having vitamin B properties such as, forexample, adenine, choline, pantothenic acid, biotin, adenylic acid,folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid,myo-inositol and lipoic acid, and vitamin C, vitamins of the D group, Egroup, F group, H group, I and J groups, K group and P group. Activeingredients for the purposes of the invention also include peptidetherapeutics and proteins. Plant treatment agents include for examplevinclozolin, epoxiconazole and quinmerac.

The process of the invention is suitable, for example, for processingthe following active ingredients:

acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, albrazolam,alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride,aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin,ampicillin, ascorbic acid, aspartame, astemizole, atenolol,beclomethasone, benserazide, benzalkonium hydrochloride, benzocaine,benzoic acid, betamethasone, bezafibrate, biotin, biperidene,bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide,bufexamac, buflomedil, buspirone, caffeine, camphor, captopril,carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefatroxil,cefazolin, cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime,celedilin, chloramphenicol, chlorhexidine, chlorpheniramine,chlortalidone, choline, cyclosporin, cilastatin, cimetidine,ciprofloxacin, cisapride, cisplatin, clarithromycin, clevulanic acid,clomibramine, clonazepam, clonidine, clotrimazole, codeine,cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone,desogestrel, dexamethasone, dexpanthenol, dextromethorphan,dextropropoxiphen, diazepam, diclofenac, digoxin, dihydrocodeine,dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine,dipyridamole, dipyrone, disopyramide, domperidone, dopamine,doxycycline, enalapril, ephedrine, epinephrine, ergocalciferol,ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide,Eucalyptus Globulus, famotidine, felodipine, fenofibrate, fenofibricacid, fenoterol, fentanyl, flavin mononucleotide, fluconazole,flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide,gallopamil, gemfibrozil, gentamicin, Gingko Biloba, glibenclamide,glipizide, clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin,haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone,hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen,imipenem, indomethacin, insulin, iohexol, iopamidol, isosorbidedinitrate, isosorbide mononitrate, isotretinoin, ketotifen,ketoconazole, ketoprofen, ketorolac, labatalon, lactulose, lecithin,levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine,lidocaine, lipase, lipramine, lisinopril, loperamide, lorazepam,lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa,methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam,minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures orcombinations and mineral salts, N-methylephedrine, naftidrofuryl,naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine,nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine,nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline,nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol,pantothenic acid, paracetamol, penicillin G, penicillin V,phenobarbital, phenoxifylline, phenoxymethylpenicillin, phenylephrine,phenylpropanolamine, phenyloin, piroxicam, polymyxin B, povidone-iodine,pravastatin, prazepam, prazosin, prednisolone, prednisone,promocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine,pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol,riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin,salicylic acid, simvastatin, somatropin, sotalol, spironolactone,sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride,tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine,tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamicacid, tretinoin, triamcinolone acetonide, triamteren, trimethoprim,troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E,volinic acid, zidovudine.

The process is particularly suitable for active ingredients having asolubility in water at 25° C. of less than 1 mg/ml. Such activeingredients are also referred to according to USP XXII, page 8, asscarcely soluble or practically insoluble.

The solid dosage forms are produced by producing, at an elevatedtemperature, i.e. a temperature at or above the softening point of theadjuvant, but at least 70° C., a moldable cohesive composition of thecomponents, which is subsequently cooled, where appropriate after ashaping step. The time for which the components are exposed to theelevated temperature is preferably less than 5 minutes, in particularless than 3 minutes, for each of the components.

The mixing of the components and the formation of the moldablecomposition can take place in various ways. The mixing can take placebefore, during and/or after the heating of one or all of the componentsof the composition, although it is not expedient to heat the crosslinkednonthermoplastic carrier in the absence of the thermoplastic componentsof the composition. For example, the components can first be mixed andthen heated to form the moldable composition. However, they can also bemixed and heated simultaneously. The moldable composition is frequentlyalso homogenized in order to obtain a highly dispersed distribution ofthe active ingredient. In the case of sensitive active ingredients,preferably the adjuvant(s) is (are) initially melted in the presence ofthe nonthermoplastic carrier and then the active ingredient is admixed.

The heating takes place in an apparatus usual for this purpose. Heatableextruders or kneaders are particularly suitable, such as mixer/kneaderreactors (e.g. ORP, CRP, AP, DTB supplied by List or Reactothermsupplied by Krauss-Maffei or Ko-kneader supplied by Buss), trough mixersand internal mixers or rotor/stator systems (e.g. Dispax supplied byIKA). The residence time of the composition in the extruder ispreferably less than 5 minutes, in particular less than 3 minutes.

Extruders which can be employed are single-screw machines, intermeshingscrew machines or else multi-screw extruders, especially twin screwextruders, corotating or counter-rotating and, where appropriate,equipped with kneading disks. Twin screw extruders of the ZSK seriesfrom Werner & Pfleiderer are particularly preferred.

The charging of the extruder or kneader takes place continuously orbatchwise according to the design thereof in a conventional way.Powdered components can be fed in freely, e.g. via a weigh feeder.Plastic compositions can be fed in directly from an extruder or fed invia a gear pump, which is particularly advantageous for high viscositiesand high pressures. Liquid media can be metered in via a suitablepumping unit.

The resulting composition is doughy or pasty. It is usually subjected toa shaping. It is possible in this way to produce a large number ofshapes, depending on the tool and mode of shaping. For example, on useof an extruder the extrudate can be shaped between a belt and a roll,between two belts or between two rolls, as described in EP-A-358 105, orby calendering in a calender with two molding rolls, see, for example,EP-A-240 904. Small-particle granules can be obtained for example byextrusion and hot or cold cut of the extrudate. The cooled compositionscan then also be ground to a powder and subsequently compressed totablets in a conventional way. It is possible in this case also to usetableting aids such as colloidal silica, calcium hydrogen phosphate,lactose, microcrystalline cellulose, starch or magnesium stearate.

The invention is illustrated in more detail by the following examples.

EXAMPLES Example 1

A mixture of 20.83% by weight of active ingredient (lopinavir), 68.17%by weight of crosslinked polyvinylpyrrolidone (Kollidon CL), 7.00% byweight of polyoxyethylene glycerol trihydroxystearate 40 (Cremophor®RH-40) and 1.00 by weight of Aerosil 200 was processed in a twin screwextruder (18 mm screw diameter) at a material temperature of 120° C. TheCremophor® RH-40 had previously been mixed at room temperature with thepowdered Kollidon CL with stirring or kneading to give free-flowinggranules, to which the active ingredient and the Aerosil 200 were thenadmixed. 1.5 kg/h of this mixture were then fed via a weigh feeder intothe extruder. A hot moldable composition in the form of a whiteextrudate emerged from the extruder head and then hardened aftercooling. The cooled extrudates (with a thickness of about 10 mm)disintegrated in water within a few minutes.

Example 2

Pieces of the extrudate obtained in example 1 were ground in alaboratory mill (from Retsch) and, after addition of 12% by weight ofcalcium hydrogen phosphate and 1% by weight of Aerosil 200 (colloidalsilica), compressed in an eccentric press (Fette E 1) to oblong tablets.The tablets showed a disintegration time of a few minutes in adisintegration test (complying with DAB) in 0.1 M hydrochloric acid at37° C.

Example 3 (Comparative Example)

Example 1 was repeated but with use of a copolymer of 60% by weight ofN-vinylpyrrolidone and 40% by weight of vinyl acetate (Kollidon VA-64)instead of Kollidon CL. A translucent extrudate emerged from theextruder head and formed a hard brittle composition after cooling. Theextrudates dissolved in water only after several hours.

Example 4 (Comparative Example)

Pieces of the extrudate obtained in example 3 were ground in analogy toexample 2 and compressed with the stated excipients to oblong tablets.The disintegration time of the tablets in a disintegration test(complying with DAB) was more than 3 hours.

Example 5

A mixture of 20.83% by weight of active ingredient (lopinavir), 61.17%by weight of crosslinked polyvinylpyrrolidone (Kollidon CL), 10.00% byweight of N-vinylpyrrolidone/vinyl acetate 60/40 copolymer (KollidonVA-64), 7.00% by weight of Cremophor RH-40 and 1.00 by weight of Aerosil200 was processed in analogy to example 1. A hot moldable composition inthe form of a white extrudate emerged from the extruder head andhardened after cooling. The cooled extrudates disintegrated in water ina few minutes.

Example 6

A mixture of 20.83% by weight of active ingredient (lopinavir), 51.17%by weight of crosslinked polyvinylpyrrolidone (Kollidon CL), 20.00% byweight of N-vinylpyrrolidone/vinyl acetate 60/40 copolymer (KollidonVA-64), 7.00% by weight of Cremophor RH-40 and 1.00 by weight of Aerosil200 was processed in analogy to example 1. A hot moldable composition inthe form of a yellowish white extrudate emerged from the extruder headand hardened after cooling. The cooled extrudates disintegrated in waterin a few minutes.

Example 7

A mixture of 20.83% by weight of active ingredient (lopinavir), 61.17%by weight of crosslinked polyvinylpyrrolidone (Kollidon CL), 10.00% byweight of N-vinylpyrrolidone/vinyl acetate 60/40 copolymer (KollidonVA-64), 7.00% by weight of sorbitan monopalmitate (Span 40) and 1.00 byweight of Aerosil 200 was processed in analogy to example 1. A hotmoldable composition in the form of a yellowish white extrudate emergedfrom the extruder head and hardened after cooling. The cooled extrudatesdisintegrated in water in a few minutes.

1. A process for producing solid dosage forms, in which a moldablecomposition which comprises a) 50 to 99.4% by weight of at least onecrosslinked nonthermoplastic carrier, b) 0.5 to 30% by weight of atleast one adjuvant selected from the group consisting of thermoplasticpolymers, lipids, sugar alcohols, sugar alcohol derivatives andsolubilizers and c) 0.1 to 49.5% by weight of at least one activeingredient, is formed at a temperature at or above the softening pointof the adjuvant, but at least 70° C., and subsequently cooled.
 2. Theprocess according to claim 1, where the composition comprises a) 50 to90% by weight of at least one crosslinked nonthermoplastic carrier, b1)5 to 30% by weight of at least one thermoplastic polymer, b2) 0.5 to 20%by weight of at least one solubilizer, c) 0.1 to 45.5% by weight of atleast one active ingredient.
 3. The process according to claim 1, wherethe crosslinked nonthermoplastic carrier is selected from the groupconsisting of crosslinked polyvinylpyrrolidone, crosslinked sodiumcarboxymethylcellulose and mixtures thereof.
 4. The process according toclaim 1, where the thermoplastic polymer is a homo- or copolymer ofvinylpyrrolidone.
 5. The process according to claim 1, where the sugaralcohol is selected from the group consisting of sorbitol, xylitol,mannitol, maltitol, the sugar alcohol derivative isomalt and mixturesthereof.
 6. The process according to claim 1, where the lipid isselected from the group consisting of fatty acids, fatty alcohols, fats,waxes, mono- and diglycerides, phosphatides and mixtures thereof.
 7. Theprocess according to claim 1, where the solubilizer is selected from thegroup consisting of sorbitan fatty acid esters, polyalkoxylated fattyacid esters, polyalkoxylated ethers of fatty alcohols and mixturesthereof.
 8. The process according to claim 1, where the activeingredient has a solubility in water at 25° C. of less than 1 mg/ml. 9.The process according to claim 1, where the cooled composition iscomminuted and compressed to the dosage form.